Natural killer (NK) cells have been recently implicated as critical modulators of adaptive immunity. In particular, NK cell interactions with dendritic cels (DCs) are central to shaping effective anti-cancer immune responses, holding great implications for DC- and other cell-based cancer immunotherapies. We have previously demonstrated that, in contrast to IL-2-activated 'killer' NK cells capable of eliminating immune-stimulatory DCs, IL-18-activated 'helper' NK cells can potentiate anti-tumor immune responses through DC activation and the enhancement of DC-induced type-1 immunity. However, our new preliminary data indicate that such IL-18- activated NK cells may also have undesirable immune-suppressive functions through the hyper-activation of myeloid-derived suppressor cells (MDSCs), reinforced by autocrine COX2-PGE2 feedback in MDSCs. This further suggests the possibility of COX2-PGE2 axis inhibition in reversing the NK-mediated up-regulation of MDSC functions, while preserving or enhancing NK-mediated DC activation. In this proposal, using IL-2- and IL-18-activated NK cells as a model, I seek to identify the mechanisms by which 'killer' and 'helper' NK cells differentially acquire and perform desirable immune-stimulatory (tumor- killing, MDSC-killing, and DC-activating) and undesirable immune-suppressive (DC-killing and MDSC- activating) functions. This mechanistic knowledge will be subsequently used to examine potential pharmacologic or biologic methods of modifying NK cell interactions with DCs and MDSCs to maximize desirable anti-cancer immune responses. Overall, this project will provide new functional and mechanistic insights into the acquisition and performance of NK cell immune-stimulatory and immune-suppressive interactions with DCs and MDSCs, and will identify targets for the therapeutic separation of these desirable and undesirable NK cell activities for the improvement of cancer immunotherapy.